An efficient method for the synthesis of 3-mercapto-1-(1,3-thiazolin-2-YL)Azetidine useful for the pendant moiety of oral carbapenem, L-084

Article abstract of DOI:10.3987/COM-06-10810

An efficient method for the synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) is described. This thiol synthesis was achieved in 3 steps from readily available 3-methanesulfonyloxyazetidine via key intermediates, Bunte salts (3 and 5). The final step was enabled to proceed under mild conditions using the benzylthiol-mediated cleavage of the S-S bond in the Bunte salt (3).{A figure is presented}.

Full text of DOI:10.3987/COM-06-10810

HETEROCYCLES, Vol. 68, No. 9, 2006
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HETEROCYCLES, Vol. 68, No. 9, 2006, pp. 1821 - 1824. © The Japan Institute of Heterocyclic Chemistry
Received, 14th June, 2006, Accepted, 3rd July, 2006, Published online, 4th July, 2006. COM-06-10810
AN EFFICIENT METHOD FOR THE SYNTHESIS OF
3-MERCAPTO-1-(1,3-THIAZOLIN-2-YL)AZETIDINE USEFUL FOR THE
PENDANT MOIETY OF ORAL CARBAPENEM, L-084
Takeshi Isoda,*a Satoshi Tamai,a Toshio Kumagai,a and Yoshimitsu Nagao*b
a
Medical Research Laboratories, Wyeth K.K., Kashiwa-cho, Shiki-shi, Saitama
353-8511, Japan
b
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
Sho-machi, Tokushima 770-8505, Japan
Email: isoda@konicaminolta.jp
Abstract – An efficient method for the synthesis of 3-mercapto-1-(1,3-thiazolin-
2-yl)azetidine (1) is described. This thiol synthesis was achieved in 3 steps from
readily available 3-methanesulfonyloxyazetidine via key intermediates, Bunte
salts (3 and 5). The final step was enabled to proceed under mild conditions using
the benzylthiol-mediated cleavage of the S-S bond in the Bunte salt (3).
3-Mercapto-1-(1,3-thiazolin-2-yl)azetidine (1)1 is exploited as the C-2 substituent of the oral carbapenem
antibiotic L-084, which is now in the clinical stage. L-084 shows a strong antimicrobial activity against
Gram-positive and Gram-negative bacteria and also exhibits a significant pharmacokinetic profile
especially in humans.2 In the course of our synthetic study of L-084 on a large scale, we required a
practical and economical process for 1 (Scheme 1). The compound (1) was previously prepared from an
oily precursor, 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine (2), obtained by adopting a roundabout
synthetic way from epichlorohydrin (31% total yield, 7 steps).2 In order to establish a new route for 1, we
designed a precursor (3) (Bunte salt) that was protected with a sulfonate group instead of an acetyl group.
Although it has been known since 1874 that the Bunte salt3 bearing a thiosulfonate function was easily
prepared at low cost using sodium thiosulfate, there have been few applications utilizing this
functionalized intermediate in organic synthesis.
We first carried out the preparation of 3 in two steps from 3-methanesulfonyloxyazetidine hydrochloride
(4)4 which was synthesized according to the literature method. Compound (4) was reacted with sodium
o
thiosulfate at 50 C in a mixture of methanol and water to afford 55 in 52% yield. At the next step, the

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HETEROCYCLES, Vol. 68, No. 9, 2006
Bunte salt (3)6 was obtained in 71% yield from the reaction of 5 and chloroethylisothiocyanate in the
presence of triethylamine in a mixture of methanol and water. While this stepwise method can be used to
prepare the desired compound (3), we envisioned that this synthesis could be achieved in the mixed
solvents in a one-pot manner. As described in the following procedure, crystalline compound (3) was
obtained in 72% yield from 4 without isolation of 5 (Scheme 1). The mixture of 4 (1.72 g, 10 mmol),
sodium thiosulfate (1.58 g, 10 mmol), methanol (2 ml) and water (8 ml) was stirred at 50 oC for 3.5 h, and
cooled to room temperature. To the reaction mixture were added chloroethylisothiocyanate (1.21 g, 10
mmol) and triethylamine (1.39 ml, 10 mmol) at room temperature. After stirring for 0.5 h, 2-propanol (10
ml) was added to the mixture, and the resulting precipitate was filtered and dried in vacuo to give 3 (gross
2.36 g, 77% purity, net 7.2 mmol). According to the sequential addition protocol, we successfully
prepared the key intermediate (3) on a multi-kilogram scale with good reproducibility.
Scheme 1
HO
H
N
H
S
N
S
N
S
N
36%
87%
O
S
N
Cl
AcS
N
HS
N
6 steps
O
2
1
CO2CH2OCOt-Bu
BnSH, NaOMe
MeOH, rt, 1 h
80%
4 steps
Ref. 4
L-084
72%
MsO
ClCH2CH2NCS
Et3N
S
N
Na2S2O3
HO3S S
N
NH
HO3S S
NH
MeOH/H2O
rt, 0.5 h
MeOH/H2O
50 oC, 3.5 h
•HCl
3 (72% from 4)
4
5
The conversion of 3 to 1 was first tried by hydrolysis.7 Although thiol (1) was obtained in 76% yield by
o
treatment under a severe acidic condition (conc. HCl, 60 C), disulfide (6) was concomitantly formed in
14% yield, and the removal of 6 from the crude product was found to be difficult.4c Because the formation
of 6 could not be suppressed under any acidic conditions, we investigated Swan’s method8 in detail to
obtain 1 selectively. The reduction method9 of the Bunte salt (RSSO3H) with thiol (R’SH), called Swan’s
method, has not been widely applied in organic synthesis because of its moderate chemoselectivity due to
a disproportionation (Scheme 2).10 Thus, we wished to optimize this reaction condition by screening
thiols (R’SH). As shown in Table 1, we evaluated four kinds of thiols, methanethiol,8b
hydroxyethanethiol,9c benzenethiol, and benzylthiol, by comparing the yields of 1. The best result was
Table 1. Reduction of 3 with various thiols and thiolatea
NaOMe (equiv.)b
Yield (%)c
74 (-)
Entry
Reagents (equiv.)
MeSNa (4)
Solvent
H2O
Time (min)
1
2
3
4
-
60
20
60
60
HOCH2CH2SH (2.1)
PhSH (3.2)
2.1
3.2
3.2
MeOH
MeOH
MeOH
53 (-)
22 (-)
BnSH (3.2)
88 (80)
aAll reactions were performed at rt. A trace amount compound (6) was ditected in all cases.
b28% Methanol solution. cHPLC yields of 1 after working up. Isolated yields are in parentheses.

HETEROCYCLES, Vol. 68, No. 9, 2006
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obtained with the use of benzylthiol (80% isolated yield as a hydrochloride salt). Sodium methylthiolate
also showed a high yield, but it failed to isolate 1·HCl as crystals. The typical procedure in order to obtain
1 is as follows: To the mixture of benzylthiol (0.94 ml, 8 mmol) and 28% NaOMe (1.53 g, 8 mmol) in
methanol (3.5 ml) was added 3 (gross 0.83 g, 77% purity, net 2.5 mmol) at room temperature, and the
mixture was stirred for 1 h. After the reaction was quenched with 2 M HCl aq (6.5 ml), the aqueous layer
was washed with CHCl3 and concentrated to dryness under reduced pressure. The crude product was
stirred in methanol, and the precipitate was removed by filtration. The filtrate was concentrated and
crystallized (CH3CN-THF) to give the hydrochloride salt of 1 (0.42 g, 80%).
Scheme 2
-
R'S
-
R'SSR'
3
R'S
HO3S S
(excess)
S
N
S
N
S
N
S
N
-
R'S S
N
S
N
S
N
N
2
-
-
7a: R' = Me
HSO3
HSO3
6
Thiolate of 1
3
R'SSR'
7b: R' = CH2CH2OH
7c: R' = Ph
7d: R' = Bn
We then extensively surveyed the reaction of 3 checking several thiols (R’SH) for 24 h on the basis of the
HPLC analysis.11 When benzylthiol was allowed to react with 3, heterodisulfide (7d)12 was obtained in low
yields (3~8%) throughout 24 h, probably due to the occurrence of a small reverse reaction of 1 to 7d. On
the other hand, heterodisulfides (7a-c)12 gradually increased to 19, 56 and 61% yields at 24 h, respectively,
accompanying the decrease in 1. Regarding the formation of 6, we found only its trace amount in each
reaction.13 We ascertained that the reaction using benzylthiol must be efficient for the further scale-up
production of 1.
In summary, an improved method for the synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1), an
important intermediate for the synthesis of L-084, has been developed. We established a practical method
for the synthesis of 1 utilizing a novel and mild deprotection procedure of the Bunte salt (3), which was
prepared economically and conveniently in a one-pot manner. The new method not only shortened the
synthesis but also improved the overall yield of 1, compared to the original method.
REFERENCES AND NOTES
1. K. Hayashi, C. Sato, S. Hiki, T. Kumagai, S. Tamai, T. Abe, and Y. Nagao, Tetrahedron Lett., 1999,
40, 3761.
2. T. Isoda, H. Ushirogochi, K. Satoh, T. Takasaki, I. Yamamura, C. Sato, A. Mihira, T. Abe, S. Tamai,
S. Yamamoto, T. Kumagai, and Y. Nagao, J. Antibiotics, 2006, 59, 241.
3. H. Bunte, Chem. Ber., 1874, 7, 646.
4. (a) A. G. Anderson and R. Lok, J. Org. Chem., 1972, 37, 3953. (b) S. Billotte, Synlett, 1998, 379. (c)

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HETEROCYCLES, Vol. 68, No. 9, 2006
T. Isoda and I. Yamamura, JP 2000355592 A2, Dec. 26, 2000 (Chem. Abstr., 2000, 134, 56662).
5. Data for 5: colorless crystals (from CH3OH-H2O), mp 225 oC (decomp.); IR (KBr) 3230, 1556, 1308,
1193, 1029 cm-1; 1H NMR (400 MHz, D2O) δ 4.19-4.27 (m, 2H), 4.44-4.54 (m, 3H); HRMS (FAB)
calcd for C3H8NO3S2 169.9946 (MW+H), found m/z 169.9932 (M++H).
6. Data for 3: colorless crystals (from CH3OH-H2O), mp 218 oC (decmp.); IR (KBr) 3129, 3041, 1656,
1453, 1242, 1205, 1024 cm-1; 1H NMR (400 MHz, CD3OD) δ 3.65 (t, J = 7.5 Hz, 2H), 4.00 (t, J =
7.5 Hz, 2H), 4.43-4.56 (m, 3H), 4.70 (dd, J = 8.4, 9.3 Hz, 2H); HRMS (FAB) calcd for C6H11N2O3S3
254.9932 (MW+H), found m/z 254.9953 (M++H).
7. (a) V. Z. El-Hewehi and E. Taeger, J. Prakt. Chem., 1958, 4, 191. (b) J. L. Kice, J. M. Anderson,
and N. E. Pawlowski, J. Am. Chem. Soc., 1966, 88, 5245. (c) T. Oguri and H. Naeka, JP 62234077
A2, Aug. 14, 1987 (Chem. Abstr., 1987, 109, 110238).
8. (a) J. M. Swan, Nature, 1957, 180, 643. (b) B. Milligan and J. M. Swan, J. Chem. Soc., 1963, 6008.
9. (a) H. Nakamura and Z. Tamura, Chem. Pharm. Bull., 1977, 25, 2369. (b) S. Inoue, M. Iwamatsu, K.
Omoto, and T. Tsuruoka, JP 54030193 A2, Mar. 6, 1979 (Chem. Abstr., 1979, 91, 91652). (c) H.
Kuroda and A. Miyadera, JP 59172460 A2, Sep. 29, 1984 (Chem. Abstr., 1984, 102, 112878).
10. (a) M. E. Alonso and H. Aragona, Org. Syn., 1978, 58, 147. (b) R. Wunderlin, S. D. Sharma, P.
Minakakis, and R. Schwyzer, Helv. Chim. Acta, 1985, 68, 12. (c) E. Kato, K. Yamamoto, T. Baba, T.
Watanabe, Y. Kawashima, H. Masuda, M. Horiuchi, M. Oya, T. Iso, and J. Iwao, Chem. Pharm.
Bull., 1985, 33, 74. (d) P. Hiver, A. Dicko, and D. Paquer, Tetrahedron Lett., 1994, 35, 9569.
11. HPLC conditions: Ultron VX-octyl 4.6 x 250 mm, 0.01 M sodium dodecyl sulfate (pH 2.2):MeCN =
1:1, 216 nm, rt, 1.4 ml/min.
12. Compounds (7a-d) were isolated as oils from each reaction mixture. Data for 7a: 1H NMR (400
MHz, CDCl3) δ 2.46 (s, 3H), 3.36 (m, 2H), 3.87-3.92 (m, 1H), 3.99-4.05 (m, 4H), 4.29 (m, 2H);
EI-MS m/z 220 (M+). Data for 7b: 1H NMR (400 MHz, CDCl3) δ 2.89 (dt, J = 5.9, 9.0 Hz, 2H), 3.36
(t, J = 7.7 Hz, 2H), 3.84-3.90 (m, 2H), 3.91-3.96 (m, 1H), 3.99-4.04 (m, 4H), 4.31 (t, J = 7.7 Hz,
1
2H); EI-MS m/z 251 (M++H). Data for 7c: H NMR (400 MHz, CDCl3) δ 3.33-3.38 (m, 2H),
3.83-4.04 (m, 5H), 4.22-4.32 (m, 2H), 7.20-7.54 (m, 5H); EI-MS m/z 282 (M+). Data for 7d: 1H
NMR (400 MHz, CDCl3) δ 3.33 (t, J = 7.5 Hz, 2H), 3.39-3.46 (m, 1H), 3.81 (dd, J = 5.6, 8.7 Hz,
2H), 3.92 (s, 2H), 4.00 (t, J = 7.5 Hz, 2H), 4.07 (dd, J = 8.4, 8.7 Hz, 2H), 7.26-7.35 (m, 5H); EI-MS
m/z 296 (M+).
13. The Bunte salt (3) was reacted with 1·HCl in the presence of NaOMe (2 equiv.) to afford 6 in 73%
isolated yield. However, it was observed that only a trace amount of 6 was formed in the reaction
shown in Scheme 2.